Small Molecule Limits MI Size in Rats

Action Points

Explain to interested patients that pretreatment with ethanol is known to reduce the size of myocardial infarcts.

Note that this study sheds light on that process.

STANFORD, Calif., Sept. 12 -- An enzyme involved in the metabolism of alcohol and a compound that can kickstart the enzyme's activity may limit the damage caused by a heart attack, researchers here said.

In a series of in vitro and animal experiments, Daria Mochly-Rosen, Ph.D., of Stanford University School of Medicine, and colleagues showed that the activity of the mitochondrial enzyme aldehyde dehydrogenase 2 is highly correlated with the extent of ischemic damage to heart muscle.

What's more, a small molecule that increases the activity of the enzyme two-fold sharply reduced the extent of damage to heart muscle, both in vitro and in experimental rats, they reported in the Sept. 12 issue of Science.

It's known that people who drink moderate amounts of alcohol tend to have less damage when they have a heart attack, the researchers said -- an effect called "pretreatment."

To see what underlies the phenomenon, they conducted a proteomic search for proteins that are turned on or off in ischemic rat hearts. The one that was consistently associated with cardioprotection was aldehyde dehydrogenase 2 (ALDH2).

"Although this enzyme was discovered a long time ago, my research group knew nothing about the enzyme except that it helps remove alcohol when people drink," Dr. Mochly-Rosen said in a statement.

But a series of tests showed that its activity was highly correlated to the size of an infarct in ischemic hearts. Indeed, linear regression yielded an inverse correlation of R2=0.95, the researchers said.

But since correlation isn't proof, the researchers searched for molecules that could increase the activity of the enzyme and a high throughput screen found a small molecule they dubbed Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide).

Treatment with the molecule reduced infarct size both ex vivo and in a live rat model of myocardial infarction, they found.

Rat hearts treated with Alda-1 before 35 minutes of ischemia followed by 60 minutes of reperfusion had a 26% smaller infarct and 24% less release of creatine phosphokinase, an indicator of cardiac damage, compared with untreated hearts. The differences were significant at P<0.05.

In the live animals, 35 minutes of ischemia and 60 minutes of reperfusion resulted in an infarct that was 43% of the left ventricular free wall.

But administration of 8.5 milligrams per kilogram of Alda-1 into the left ventricle five minutes before ischemia decreased the MI by 60%, which was significant at P<0.01.

One of the molecules produced during cardiac damage is a toxic aldehyde called 4-hydroxynonenal. Its removal by aldehyde dehydrogenase 2 may be one of the ways the enzyme prevents damage, the researchers theorized.

Interestingly, 4-hydroxynonenal itself can inactivate the enzyme, limiting its own removal, but the researchers found that Alda-1 blocks that inactivation.

Because Alda-1 is small, it should be easy to adapt for pharmacological use, Dr. Mochly-Rosen said, adding she thinks "it has a huge potential use" in removing aldehydes associated with other conditions.

In further exploration of ALDH2 and cardioprotection, the authors pointed out that prolonged nitroglycerin treatment confers protection if it's terminated at least an hour before the ischemic event, but will increase the damage if it's continued through the event.

They gave an example: "We found that 13 hours of nitroglycerin treatment that was terminated three hours before the ischemic event decreased cardiac infarct size from 45% to 33%. However, similar to our ex vivo data, when the nitroglycerin patch was left on, infarct size increased from 45% to 59%."

The reason for the increased damage, they theorized, was inactivation of ALDH2.

That activity of nitroglycerin could have important clinical implications for East Asian patients who carry a mutant form of ALDH2 dubbed ALDH2*2, which has no more than 5% of the catalytic activity of the wild-type ALDH2*1 form.

Alda-1 increased the activity of the mutant ALDH2*2 11-fold.

So, the researchers concluded, the data "suggest that the prolonged use of nitroglycerin in East Asian carriers of ALDH2*2 who experience an ischemic event may need to be reconsidered and that these patients may benefit even more than carriers of the wild-type enzyme if treated with ALDH2 activators."

The study was supported by the National Institute on Alcohol Abuse and Alcoholism and Stanford University.

The researchers did not report any conflicts.

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine

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